Bismuth Containing Liquid Pharmaceutical Suspensions

ABSTRACT

A liquid pharmaceutical suspension for oral administration containing a bismuth-containing pharmaceutical agent, a suspension system, and water. The suspension system can contain from about 0.001% to about 0.2% gellan gum and from about 0.001% to about 0.75% magnesium aluminum silicate.

FIELD OF THE INVENTION

The present invention relates to liquid pharmaceutical formulationscontaining bismuth, particularly bismuth-containing pharmaceuticalformulations that have improved stability and rheological properties.

BACKGROUND OF THE INVENTION

Bismuth is a common active in over-the-counter liquid pharmaceuticalformulations. Pharmaceutical formulations containing bismuth are oftensold as suspensions (e.g. Pepto-Bismol®, distributed by Procter &Gamble®) and can be used to treat gastrointestinal symptoms includingnausea, heartburn, indigestion, upset stomach, and diarrhea.

It can be difficult to formulate bismuth-containing suspensions that arepH stable, physically stable, and have a rheology that is consumeracceptable. Some currently available formulations exhibit an upward pHdrift, shortening the product's shelf-life. Other bismuth-containingliquid formulations can suffer from physical instability and canseparate into phases, during storage or under freeze-thaw conditionsthat can be encountered during shipping and handling, which results inan appearance that is unacceptable to consumers. Furthermore, someconsumers do not prefer the rheology of current bismuth products, as theproduct can have non-uniform viscosities, which can result in an uneven,gloppy, pour, making it more difficult to measure the dose and pourwithout spilling.

However, it is difficult to improve the stability and rheology ofbismuth-containing formulations because small formulation changes cansignificantly impact the formulation's properties and can evenexacerbate the stability and/or rheology problems.

As such, there remains a need for a suspension that has improved pHstability, physical stability, and rheology properties.

SUMMARY OF THE INVENTION

A liquid pharmaceutical suspension for oral administration comprising:(a) a bismuth-containing pharmaceutical agent; (b) a suspension systemcomprising from about 0.001% to about 0.2% gellan gum and from about0.001% to about 0.75% magnesium aluminum silicate; (c) water.

A liquid pharmaceutical suspension for oral administration comprising:(a) a bismuth-containing pharmaceutical agent; (b) a suspension systemcomprising gellan gum; (c) water.

A liquid pharmaceutical suspension for oral administration comprising:(a) a bismuth-containing pharmaceutical agent; (b) a suspension system;(c) water; wherein the formulation comprises less than about 0.2 ppmlead and wherein the liquid formulation has no more than slightsedimentation is visually perceptible after 30 days at 40° C.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is a chemical structure of gellan gum.

DETAILED DESCRIPTION OF THE INVENTION

Bismuth-containing pharmaceutical formulations are often sold assuspensions.

However, the pH stability, physical stability, and rheology of currentformulations can be improved. The current United States Pharmacopeia(USP) Monograph requires that liquid bismuth products have a pH between3.0 and 5.0. Some current formulations can have an upward pH drift thatcan decrease their shelf life. Furthermore, current formulations canalso have problems with physical stability and can separate into phasesduring storage and handling, resulting in an appearance that can beundesirable to consumers. To mitigate the physical instability problems,a consumer can shake the bottle to ensure good mixing before use.Bismuth formulations can also have non-uniform viscosities, even aftershaking, which can result in an uneven, gloppy, pour, making it moredifficult to measure the dose and pour without spilling.

Altering the liquid formulation to improve the stability and rheologycan be difficult because even small formulation changes, can negativelyaffect the taste, mouthfeel, rheology, and pH of the formulation.However, it has been found that making certain adjustments to theexcipients, in particular the suspension system, can improve the pHstability, physical stability, and/or rheology of the bismuthformulations.

In one example, it was found that the formulation, particularly therheology and physical stability, can be improved if the suspensionsystem includes magnesium aluminum silicate, methyl cellulose, andgellan gum. It was surprisingly found that these three components mayhave a synergestic effect when used in combination. The methyl cellulosecan help improve the initial viscosity of the formulation at 0.1 s⁻¹shear rate and a higher initial viscosity can help to improve theformulation's initial physical stability, as well as the physicalstability over an extended time. The suspension system can also increasethe viscosity of the solution over an extended time. In some examples,the initial viscosity can be higher than the viscosity over an extendedtime. In some examples, it was found that adding a small amount ofmagnesium aluminum silicate, can help to make the suspension more stableover an extended period of time. It was also found that consumersthought that formulations which included gellan gum had improvedcharacteristics including mouthfeel, ease of swallowing, smoothness,ease of pour, and aftertaste.

In one example, the bismuth-containing liquid pharmaceutical suspensioncan contain from about 0.05% to about 0.75% magnesium aluminum silicate,from about 1.5% to about 2.25% methyl cellulose, and from about 0.015%to about 0.5% gellan gum. The liquid-formulation can have an the initialviscosity at 0.1 s⁻¹ shear rate of greater than about 2,000 cps and inanother example greater than 5,000 cps. The pH drift over 180 days canbe from about 0.1 to about 0.8. In one example, the preservative systemcan contain benzoic acid and optionally sorbic acid.

In another example, it was found that reducing the amount of magnesiumaluminum silicate, from the level found in some current formulations,can reduce the upwards pH drift. In one example, the suspension systemcan contain less than about 0.2% magnesium aluminum silicate and canhave a pH drift of less than 0.1 over 180 days.

In another example, the bismuth-containing liquid pharmaceuticalsuspension can have a suspension system that can include gellan gumand/or methyl cellulose, and no magnesium aluminum silicate and can havea pH drift of less than about 0.1 over 180 days. In one example, thepreservative system can contain benzoic acid and optionally sorbic acid.

As used herein, “daily intake” or “permissible daily exposure” refers tothe intake level of a nutrient, chemical element, or pharmaceuticalactive over a 24 hour period.

As used herein, “dose” refers to a volume of the liquid formulationcontaining an amount of a drug active suitable for administration on asingle occasion, according to sound medical practice. A dose can beorally administered and is typically swallowed immediately. In oneexample, a dose can be about 30 mL, in another example about 25 mL, inanother example about 20 mL, in another example about 15 mL, and inanother example about 10 mL. The concentration of active ingredients canbe adjusted to provide the proper doses of actives given the liquid dosesize.

The term “pharmaceutically-acceptable”, as used herein, means that thecomponents present in the formulations of the present invention arecompatible and suitable for oral administration to a human or mammal.The term “compatible”, as used herein, means that the components of thepharmaceutical formulations are capable of being commingled with eachother in a manner such that there is no interaction which wouldsubstantially reduce the pharmaceutical efficacy of the pharmaceuticalformulations, or the effectiveness of the preservatives, under ordinaryuse situations. Pharmaceutically-acceptable components for use hereinmust, of course, be of sufficiently high purity and sufficiently lowtoxicity to render them suitable for oral administration to the human ormammal being treated.

In one example, the liquid medication can contain 525 mg bismuthsubsalicylate (BSS) per 30 mL dose. In one example, adults and children12 years and over can consume one dose (30 mL) every half hour to houras needed. Users should not ingest more than 8 doses (240 mL) in atwenty-four hour period. Users with diarrhea can follow these directionsand use until the diarrhea stops, but not for more than two days. Inanother example, children under 12 and adults can consume the liquidmedication.

In another example, the liquid medication can contain 1050 mg BSS per 30mL dose. Adults and children 12 years and over can consumer one dose (30mL) every hour as needed. Users should not ingest more than 4 doses (120mL) in a twenty-four hour period. In another example, children under 12and adults can consume the liquid medication.

In one example, the formulation can have a lead level below a certainthreshold. The lead level of the formulation and/or the individualcomponents can be measured by any method that satisfies USP <233>Elemental Impurities—Procedures as described in the Second Supplement toUSP 35-NF. In one example, the daily intake can be 120 mL and in anotherexample the daily intake can be 240 mL. In one example, the formulationcontains less than about 1 ppm lead, in another example less than about0.7 ppm lead, in another example less about 0.5 ppm lead, in anotherexample less than about 0.4 ppm lead, in another example less than about0.3 ppm lead, in another example less than about 0.2 ppm lead, inanother example less than about 0.1 ppm lead, in another example lessthan about 0.05 ppm lead, and in another example less than about 0.025ppm lead. In one example, the formulations can have a daily intake ofless than about 40 μg/day lead, in another example less than about 38μg/day lead, in another example less than about 35 μg/day lead, inanother example less than about 30 μg/day lead, in another example lessthan about 20 μg/day lead, in another example less than about 15 μg/daylead, in another example less than about 10 μg/day lead, and in anotherexample less than about 5 μg/day lead. In one example, the formulationscan have a daily intake of less than about 5 μg/day lead. In oneexample, the liquid formulation contains less than 40 μg lead per 240mL, in another example less than about 20 μg lead per 240 mL, in anotherexample less than about 10 μg per 240 mL, and in another example lessthan about 5 μg per 240 mL. In one example, the liquid formulationcontains less than about 45 μg lead per 120 mL, in another example lessthan about 30 μg lead per 120 mL, in another example less than about 15μg per 120 mL, and in another example less than about 5 μg lead per 120mL. In another example, the volume of liquid formulation that has 4200mg bismuth contains less than about 40 μg lead, in another example lessthan about 20 μg lead, in another example less than about 10 μg, and inanother example less than about 5 μg lead.

Bismuth-Containing Pharmaceutical Agent

The pharmaceutical formulations of the present invention comprise abismuth-containing pharmaceutical agent, which can be in the form of apharmaceutically-acceptable salt. Non-limiting examples ofbismuth-containing pharmaceutical agents can include bismuth aluminate,bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassiumdicitrato bismuthate, bismuth subgalate, bismuth subnitrate, bismuthtartrate, bismuth subsalicylate, and mixtures thereof. In one example,the pharmaceutical formulation can contain bismuth subsalicylate (BSS).

The liquid pharmaceutical formulations of the present invention cancontain from about 0.1% to about 10% of a bismuth-containingpharmaceutical agent, in another example from about 0.5% to about 5%, inanother example from about 1% to about 4%, and in another example fromabout 1.5% to about 2.5%. In another example the formulation can containfrom about 0.2% to about 8% of a bismuth-containing pharmaceuticalagent, in another example from about 1% to about 6%, and in anotherexample from about 2% to about 4%.

Suspension System

The formulations can also contain a suspension system capable ofsuspending the bismuth-containing pharmaceutical agent and the othercomponents in an aqueous media.

In one example, the suspension system can contain gellan gum, magnesiumaluminum silicate (commercially available as Veegum® and manufactured byVanderbilt Minerals, LLC), a pharmaceutically-acceptable non-ioniccellulose ether polymer, or mixtures thereof.

In one example, the weight ratio of gellan gum to magnesium aluminumsilicate is from about 1.0 to about 0.01, in another example from about0.8 to about 0.1, in another example from about 0.5 to about 0.01, inanother example from about 0.3 to about 0.05, in another example fromabout 0.25 to about 0.1, and in another example from about 0.15 to about0.1. In another example, the weight ratio of gellan gum to methylcellulose is from about 0.01 to about 0.1, in another example from about0.015 to about 0.05, in another example from about 0.02 to about 0.04,in another example from about 0.025 to about 0.08, and in anotherexample 0.03 to about 0.06. In another example the weight ratio ofmethyl cellulose to magnesium aluminum silicate is from about 6 to about15, in another example from about 8 to about 12, and in another examplefrom about 9 to about 11. In another example, the weight ratio of methylcellulose to magnesium aluminum silicate is from about 1.5 to about 11,in another example from about 2 to about 7, and in another example fromabout 3.5 to about 6. In another example, the weight ratio of magnesiumaluminum silicate to bismuth is from about 0.01 to about 0.5, in anotherexample from about 0.01 to about 0.03, in another example from about0.01 to about 0.2, in another example from about 0.02 to about 0.15, inanother example from about 0.02 to about 0.1, and in another examplefrom about 0.02 to about 0.08. In another example, the weight ratio ofmagnesium aluminum silicate to bismuth is from about 0.05 to about 0.15.

In one example, the suspending system can have a suspending agent with ahigh molecular weight. In one example, the molecular weight of thesuspending agent is greater than about 500,000 Daltons, in anotherexample greater than about 1 million Daltons, in another example greaterthan about 1.5 million Daltons, and in another example greater thanabout 2 million Daltons.

In another example, the suspension system can have a suspending agentthat is charged. In one example, the suspension agent can have ananionic charge and in another example the suspension agent can have acationic charge.

In one example, a suspending agent is gellan gum. The FIGURE shows thechemical structure of gellan gum. The CAS# for gellan gum is 71010-52-1.Gellan gum is a heteropolysaccharide prepared by fermentation ofPseudomonas elodea ATCC 31461. Gellan gum is available from KelcoDivision of Merck & Co., Inc., San Diego, Calif., under various names,including Kelcogel®.

Gellan gum is a linear, repeating polymer consisting of glucose,rhamnose, and glucuronic acid in the tetrasaccharide repeating unit. Itcan also exist in either its native high acyl form or a synthetic lowacyl form in which all acyl groups have been removed. In the high acylform of Gellan gum, the glucose portion of the repeating tetrasaccharideunit possesses an acetate and a glycerate group on the same residue. Onaverage, there is one glycerate and 0.5 acetate per repeatingtetrasaccharide unit.

In some examples, gellan gum can help create a unique suspension systemvia the formation of a uniquely functioning “fluid gel” solution with aweak gel structure. In one example, a suspension system that containsgellan gum can also be more physically stable than one without. In oneexample, liquid formulations that contain a suspension system withgellan gum can have a high, low-shear viscosity, which can provide goodsuspension properties, even at a low concentration. In another example,gellan gum can help form highly pseudo plastic or thixotropicformulations.

In one example the liquid formulation can contain from about 0.001% toabout 0.1% gellan gum, in another example from about 0.005% to about0.06%, in another example from about 0.01% to about 0.05%, and inanother example 0.02% to about 0.04%. In another example the liquidformulation can contain from about 0.007% to about 0.2% gellan gum, inanother example from about 0.013% to about 0.17% gellan gum, in anotherexample from about 0.015% to about 0.15% gellan gum, and in anotherexample from about 0.017% to about 0.12% gellan gum. In another example,the composition can contain from about 0.005% to about 1% gellan gum, inanother example from about 0.01% to about 0.75% gellan gum, in anotherexample from about 0.16% to about 0.6%, in another example from about0.2% to about 0.5%, and in another example from about 0.3% to about0.4%. In one example, the suspension system can contain only gellan gum.In another example, the suspension system can contain only gellan gumand methyl cellulose and in another example the suspension system cancontain only gellan gum, methyl cellulose, and magnesium aluminumsilicate.

In one example, the suspension system can contain magnesium aluminumsilicate, with the chemical formula Al₂MgO₈Si₂, which occurs naturallyin such smectite minerals as colerainite, saponite, sapphirine, andmontmorillonite. Some currently available liquid pharmaceuticalsuspensions that contain bismuth contain magnesium aluminum silicate,for instance about 1.0% magnesium aluminum silicate. However,formulating with this level of magnesium aluminum silicate cancontribute to the upward pH drift and the non-homogenous viscosities.Thus, it can be preferable to formulate with a small amount of magnesiumaluminum silicate or even without magnesium aluminum silicate.

In one example, the magnesium aluminum silicate can be made frompurified bentonite and thus can have no detectable levels of calciumcarbonate. In another example, the magnesium aluminum silicate containsonly montmorillonite. In another example, the magnesium aluminumsilicate can contain both montmorillonite and saponite.

In one example, the formulation can contain from about 0.001% to about0.5% magnesium aluminum silicate, in another example from about 0.01% toabout 0.25%, in another example from about 0.05% to about 0.2%, and inanother example from about 0.075% to about 0.125%. In one example, theformulation can contain from about 0.005% to about 1% magnesium aluminumsilicate, in another example from about 0.1% to about 0.8%, in anotherexample from about 0.2% to about 0.6%, and in another example from about0.3% to about 0.5%. In one example the formulation contains about 1% orless magnesium aluminum silicate, in another example about 0.75% orless, in another example about 0.5% or less, and in another exampleabout 0.4% or less. In one example the formulation contains about 0.3%or less magnesium aluminum silicate, in another example about 0.25% orless, in another example about 0.2% or less, in another example about0.15% or less, in another example about 0.10% or less, in anotherexample about 0.05% or less. In one example, the formulation is free ofmagnesium aluminum silicate.

In another example, the suspension system can comprise a non-ioniccellulose ether polymer. Non-limiting examples of non-ionic celluloseether polymers can be selected from the group consisting ofalkylcelluloses (e.g., methyl cellulose), hydroxyalkylalkylcelluloses(e.g., hydroxypropylmethyl cellulose: hydroxybutylmethyl cellulose;hydroxyethylmethyl cellulose; ethylhydroxyethylcellulose),hydroxyalkylcelluloses (e.g., hydroxyethylcellulose;hydroxypropylcellulose), carboxymethyl cellulose sodium,microcrystalline cellulose, a combination of carboxymethyl cellulosesodium and microcrystalline cellulose (e.g. Avicel RC-591 of FMC Corp.),and mixtures thereof. In one example, the formulation can containalkylcelluloses. In one example, the formulation can contain methylcellulose. In one example, the formulation can contain from about 0.1%to about 5% non-ionic cellulose ethyl polymer, in another example fromabout 0.1% to about 3%, in another example from about 0.5% to about1.5%, and in another example from about 0.75% to about 1.3%.

In another example, the suspension system can include a componentselected from the group consisting of carboxymethyl cellulose sodium,microcrystalline cellulose, a combination of carboxymethyl cellulosesodium and microcrystalline cellulose, xanthan gum, silicon dioxide, andmixtures thereof.

In another example, the suspension system can contain xanthan gum. Sincexanthan gum is a high molecular weight polysacchride produced throughpure culture fermentation of carbohydrates by the microorganismXanthomonas camoestris, it does not contain measurable quantities oflead. In one example, the formulation can contain from about 0.1% toabout 5% xanthan gum, in another example from about 0.1% to about 3%,and in another example from about 0.5% to about 1.5%.

In another example, the suspension system can include a synthetic clay.

In another example, the suspension system can contain a synthetic clay,such as lithium magnesium sodium silicate (commercially available asLaponite™ from BYK-Chemie GmbH, Germany) Non-limiting examples ofsynthetic clays can include lithium magnesium silicate, lithiummagnesium sodium silicate, and combinations thereof.

In another example, the suspension system can include bentonite, whichare absorbent aluminum phyllosilicates.

In another example the suspension system can include clay mineralsselected from the kaolin group which can include the minerals kaolinite,dickite, halloysite, and/or nacrite; the smectite group which caninclude dioctahedral smectites such as montmorillonite, nontronite,and/or trioctahedral smectites; the illite group which can includeclay-micas; the chlorite group; attapulgite clays; sepiolite; andcombinations thereof.

In another example, the suspension system can contain less than about 20ppm lead, in another example less than about 15 ppm lead, in anotherexample less than about 10 ppm lead, in another example less than 7 ppmlead, and in another example less than 5 ppm lead. In one example thesuspension system can contain from about 1 ppm lead to about 13 ppmlead, in another example from about 5 ppm to about 11 ppm lead, and inanother example from about 6.5 ppm lead to about 9.5 ppm lead.

Buffers

The liquid pharmaceutical formulation can contain a buffer. The buffercan help keep the pH within a desired range. The pH of the formulationcan be from about 3.0 to about 5.0. The pH can be measured using the pHMethod, described hereafter.

The initial pH, which can be measured soon after the formulation ismade, can be from about 3 to about 4.2, in another example from about3.05 to about 3.7, in another example from about 3.1 to about 3.4, andin another example from about 3.1 to about 3.3. The 36 day pH can befrom about 3.0 to about 4.5, in another example from about 3.1 to about4.0, in another example from about 3.1 to about 3.8, and in anotherexample from about 3.2 to about 3.4. The 36 day pH is measured after theformulation is stored in a closed PET bottle for 36 days at ambienttemperature out of direct sunlight.

In one example, the formulations can have an upward pH drift, whencomparing the change in pH from the pH at 36 days to the initial pH. Inone example, the pH change over 36 days is from about 0.02 to about 0.5,in another example from about 0.05 to about 0.4, and in another examplefrom about 0.1 to about 0.3. In one example, the pH change over 36 daysis less than about 0.4, in another example less than about 0.3, inanother example less than about 0.2, and in another example less thanabout 0.1. In another example, the pH change over 36 days is greaterthan about 0, in another example greater than about 0.03, in anotherexample greater than about 0.1, and in another example greater thanabout 0.18. The pH can be determined by the pH Test Method, describedhereafter.

In one example, the pH change over 180 days is from about 0.02 to about1, in another example from about 0.1 to about 0.8, and in anotherexample from about 0.2 to about 0.6. In one example, the pH change over180 days is less than about 0.9, in another example less than about 0.7,in another example less than about 0.6, in another example less thanabout 0.5, in another example less than about 0.3, and in anotherexample less than about 0.1. In another example, the pH change over 180days is greater than about 0, in another example greater than about0.15, and in another example greater than about 0.3. The pH can bedetermined by the pH Test Method, described hereafter.

In one example the liquid medication can contain from about 0.001% toabout 1% buffer, in another example from about 0.01% to about 0.5%buffer, in another example from about 0.02% to about 0.3% buffer, and inanother example from about 0.05% to about 0.15% buffer. Non-limitingexamples of buffers can include acetic acid, sodium acetate, citricacid, sodium citrate, monobasic sodium phosphate, dibasic sodiumphosphate, sodium carbonate, sodium bicarbonate, succinic acid, sodiumsuccinate, potassium dihydrogen phosphate, phosphoric acid, salicylicacid, and combinations thereof.

In another example, the buffer can contain salicylic acid. In oneexample the formulation can contain from about 0.01% to about 0.5%salicylic acid, in another example from about 0.03 to about 0.25%, andin another example 0.05% to about 0.1%.

Preservative

The liquid pharmaceutical formulation can contain a preservative.Non-limiting examples of preservatives can include benzalkoniumchloride, ethylenediaminetetraacetic acid (EDTA), benzyl alcohol,potassium sorbate, parabens, benzoic acid, sorbic acid, sodium benzoate,and mixtures thereof. The formulation can contain from about 0.01% toabout 0.5% preservative, in another example from about 0.02% to about0.1%, and in another example from about 0.03% to about 0.05%.

In one example, the liquid pharmaceutical formulation can containbenzoic acid or a pharmaceutically-acceptable salt of benzoic acid. Inone example the formulation can contain from about 0.01% to about 0.2%benzoic acid, in another example from about 0.01% to about 0.1%, and inanother example from about 0.015% to about 0.03%. In one example, theonly buffer in the formulation can be benzoic acid.

In another example, the liquid pharmaceutical formulation can containsorbic acid or a pharmaceutically-acceptable salt of sorbic acid. In oneexample the formulation can contain from about 0.01% to about 0.1%sorbic acid, in another example from about 0.01% to about 0.08%, inanother example from about 0.01% to about 0.04%, and in another examplefrom about 0.0125% to about 0.04%.

In one example, the only preservative in the formulation can be benzoicacid. In another example, the formulation can contain two preservatives,sorbic acid and benzoic acid.

Water

The liquid formulations of the present invention can further comprisefrom about 80% to about 99% water, in another example from about 90% toabout 99%, and in another example from about 93% to about 98%.

Optional Components

In addition to the components described hereinbefore, the pharmaceuticalformulations can contain additional optional components selected asappropriate for the particular formulation being prepared. The choice ofpharmaceutically-acceptable optional components to be used in theformulations of the present invention is basically determined by theproperties, especially aesthetic properties, desired for theformulation. Pharmaceutically-acceptable optional components suitablefor the preparation of formulations herein for oral administration arewell known in the art.

Some examples of substances that can serve aspharmaceutically-acceptable optional components are sugars such aslactose, glucose and sucrose; non-nutritive sweeteners such assaccharin, aspartame, acesulfame, sucralose, and cyclamate; coloringagents; flavoring agents such as methyl salicylate, peppermint andcherry flavor; etc. In one example, the sweetener is sucralose. Inanother example, the sweetener does not contain saccharin.

Other compatible pharmaceutical additives and actives (e.g.,non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, andnaproxen; acetaminophen; H₂ receptor antagonists; antacids) may beincluded in the pharmaceutically-acceptable optional components for usein the formulations of the present invention.

In another example, the bismuth-containing formulation has less than 25ppm cadmium per daily intake, less than 15 ppm inorganic arsenic perdaily intake, less than 15 ppm inorganic mercury per daily intake, lessthan 100 ppm iridium, osmium, palladium, platinum, rhodium, ruthenium,or molybdenum per daily intake, and/or less than 500 ppm nickel perdaily intake. Additional information on elemental impurities can befound in USP <232> Elemental Impurities—Limits as described in SecondSupplement to USP 35-NF. The level of elemental impurities in theformulation and/or the individual components can be measured by anymethod that satisfies USP <233> Elemental Impurities—Procedures asdescribed in the Second Supplement to USP 35-NF.

Examples

For the following examples, the methyl cellulose was supplied byHercules Aqualon a subsidiary of Ashland®, Inc. (Wayne, N.J.). Themagnesium aluminum silicate is commercially available as Veegum® HV fromVanderbilt Minerals, LLC (Murray, Ky., USA), unless it is specified thatit is Veegum® N, which is also available from Vanderbilt Minerals. Thegellan gum is commercially available as Kelogel® CG-HA from CP Kelco(Atlanta, Ga.).

Examples 1-10, 18-19, and A-Q were made as follows. First, threepremixes or slurries were made. The dye premix was made by adding colorto water and heating and stirring until dissolved.

Separately, a minors premix was made by adding the flavor, salicylicacid, sodium salicylate, sweeteners, benzoic acid, and sorbic acid towater and heating and stirring until the solution became clear.

Separately, a BSS slurry was made by adding BSS powder to water underhigh shear.

To make the examples, the first step was to add the suspension systemcomponents to water. Each suspension system component, if present, wasadded to water under high shear mixing: magnesium aluminum silicate,methyl cellulose, and finally gellan gum. Then, under low shear mixingthe dye premix, the BSS slurry, and the minors premix were added. ThenQ.S. of water was added to form the final bismuth-containingpharmaceutical formulation.

In the first example, a taste test was performed with 10 male consumerpanelists. Each panelist ingested 30 mL of five blinded samples in arandomized order. Four of the samples correspond to Examples 1 to 4, asdescribed below in Table 1B, and one commercial product was used,Pepto-Bismol®. All samples were original flavor and regular strength.Each panelist sampled one example per day for five days.

Panelists poured a 30 mL dose from a container and then ingested thedose Immediately following ingestion, panelists completed aquestionnaire where they rated the product they had just tasted foroverall rating and liking as well as various characteristics. Panelistsalso rated the aftertaste 15 and 30 minutes after ingesting the product.Panelists were instructed not to eat or drink anything other than wateruntil after they had completed the questions related to aftertaste. Thepanelists gave each formulation a qualitative rating of excellent, verygood, good, fair, or poor based on his overall rating based onperception and taste of the sample. Then, the ratings were converted toa numerical value and the mean was calculated. An excellent ratingscored 100, very good scored 75, good scored 50, fair scored 25, andpoor scored 0.

The average overall rating and average ratings for each characteristiccan be seen in Table 1A, below.

TABLE 1A Ex. 5 Ex. 1 Ex. 2 Ex. 3 Ex. 4 Current Pepto¹ Overall Rating67.5 45.0 70.0 57.5 60.0 Overall Mouth 62.5 52.5 62.5 62.5 57.5 FeelEase of Swallow 67.5 57.5 70.0 70.0 60.0 Chalkiness Level 52.5 62.5 60.066.7 62.5 Thickness 55.0 47.5 57.5 55 62.5 Smoothness 75.0 65.0 70.070.0 55.0 Coating of 56.2 66.7 58.3 61.1 63.9 Throat Overall 67.5 57.565.0 66.7 52.5 Appearance Ease of Pour 70.0 65.0 67.5 70.0 55.0 OverallFlavor 62.5 50.0 62.5 47.2 67.5 Aftertaste 55.0 47.5 62.5 44.4 57.5 Odor65.0 62.5 65.0 58.3 67.5 Sourness 55.0 45.0 50.0 37.5 57.5 Sweetness55.0 55.0 55.0 45.0 60.0 ¹Lot # 2296 171951, Expiration September 2014

TABLE 1B Ex. 1 Ex. 2 Ex. 3 Ex. 4 BSS 1.7305% 1.7305% 1.7305% 1.7305%Methyl cellulose  1.086%  1.086%  1.086%  1.086% Magnesium    0%    0%  0.1%    0% aluminum silicate Magnesium 0.9924%    0%    0%    0%aluminum silicate² Gellan gum    0%  0.05%  0.025% 0.0375% Benzoic Acid 0.025%  0.025%  0.025%  0.025% Sorbic Acid 0.0126% 0.0126% 0.0126%0.0126% Salicylic acid  0.071%  0.071%  0.071%  0.071% Sweetener 0.0604%0.0604% 0.0604% 0.0604% Color 0.0124% 0.0124% 0.0124% 0.0124% Flavor0.0888% 0.0888% 0.0888% 0.0888% Distilled Water Q.S. Q.S. Q.S. Q.S.Initial pH (neat) 3.67 3.09 3.17 3.07 36 day pH (ambient 4.09 3.13 3.373.12 storage, neat) Change in pH (36 0.42 0.04 0.20 0.05 day pH −initial pH) ²Commercially available as Veegum ® N

Example 3 had an improved overall experience versus commercialPepto-Bismol®. This formula was rated directionally higher than thecommercial control overall and for mouthfeel, ease of swallowing,smoothness, ease of pour, and aftertaste. Example 4 was perceivedsimilarly to Example 3 for mouthfeel, ease of swallowing, etc., howeverhad lower ratings for overall flavor, aftertaste, odor, sourness, andsweetness. Thus, adding 0.1% magnesium aluminum silicate can favorablyimpact the overall experience of the liquid medication.

A second taste test was performed with 116 consumer panelists (43% male,57% female, aged 22 to 59). In this test, each panelist ingested 30 mLof five blinded samples in a randomized order. Three of the samplescorrespond to Examples 6, 7, and 8, as described below in Table 2B, andtwo commercial products were used, Pepto-Bismol® and Kroger® LiquidStomach Relief. All samples were original flavor and regular strength.Panelists were given twelve days to complete the panel and almost allpanelists tasted one sample per day with the exception of eightpanelists who tasted two samples in a day.

The test was done approximately the same as described above, except eachpanelist was given 40 mL of the sample in a small cup and asked tomeasure a 30 mL dose into a standard dose cup and then ingest the 30 mLdose Immediately following ingestion, panelists completed the samequestionnaire as described above.

The average overall rating and average ratings for each characteristiccan be seen in Table 2A, below.

TABLE 2A Ex. 9 Ex. 10 Pepto- Kroger ® Liquid Ex. 6 Ex. 7 Ex. 8 Bismol ®Stomach Relief Overall Rating 45 62 54 53 49 Overall Mouth 49 63 60 5449 Feel Ease of Swallow 61 71 64 61 58 Chalkiness Level 48 60 55 50 41Thickness 51 61 57 53 50 Smoothness 57 68 63 61 60 Coating of 54 64 6259 57 Throat Overall 39 63 56 49 43 Appearance Ease of Pour 59 64 65 6060 Overall Flavor 39 63 56 49 43 Aftertaste 41 54 50 43 39 Odor 57 65 6456 57 Sourness 43 61 54 51 48 Sweetness 45 65 58 54 45 ³Lot # 2296171951, Expiration September 2014 ⁴Lot #AK0329

TABLE 2B Ex. 6 Ex. 7 Ex. 8 BSS 1.7305% 1.7305% 1.7305% Methyl cellulose1.0860% 1.0860% 1.0860% Magnesium 0.1000% 0.1000%    0% aluminumsilicate Gellan gum 0.0250% 0.0250% 0.0375% Benzoic Acid 0.0250% 0.0250%0.0250% Sorbic Acid 0.0126% 0.0126% 0.0126% Salicylic acid 0.0594%0.0594% 0.0594% Sodium Salicylate 0.0738% 0.0738% 0.0738% Sweetener0.0612% 0.0612% 0.0612% Color 0.0124% 0.0124% 0.0124% Flavor 0.0888%0.0888% 0.0888% Distilled Water Q.S. Q.S. Q.S.

Example 7 had the highest overall rating by the panelists and alsoranked the highest for most of the other product characteristics.Furthermore, Example 7 was perceived as being approximately equal to ormore favorable for all characteristics when compared to currentPepto-Bismol®. In particular, Example 7 was rated less chalky, lessaftertaste, less sour, and better overall flavor than currentPepto-Bismol®. Example 8, which did not have magnesium aluminumsilicate, was less desirable by consumers than Example 7 and had a lessdesirable taste and the components also fell out of the suspension.

The next example compares the initial viscosity of compositions withdifferent suspension systems. The initial viscosity, in particular theinitial viscosity at 0.1 s⁻¹, affects the physical stability of theliquid pharmaceutical composition. A higher initial viscosity at 0.1 s⁻¹shear rate can improve the formulation's physical stability.

Some current liquid bismuth formulations have a suspension system thatcontains magnesium aluminum silicate and methyl cellulose and canexhibit low level physical instability. This means that after aboutthree to six months of storage, a clear ring can form at the top of theliquid and a precipitate of large clusters of bismuth crystals cancollect at the bottom of the bottle. Although, consumers can shake thebottle to ensure good mixing before ingesting the contents, the bismuthformulations can look less appealing on the store shelf or inside theconsumer's medicine cabinet. Furthermore, the separation, even aftershaking, can cause the liquid composition to have non-uniformviscosities which can result in an uneven, gloppy, pour, making it moredifficult to measure the dose and pour without spilling and unpleasantmouthfeel.

Table 3A, below, shows the formulations for Examples 11-17. Examples11-17 do not contain actives or additional excipients. Examples 11-17were made by adding each component of the suspension system to waterunder high shear mixing. Then, Q.S. of water was added to form the finalformulation.

Table 3B, below, shows the initial viscosity of Examples 11-17 atdifferent shear rates. The materials added in Table 3A, correspond tothe suspension system of the finished product in Table 3B.

TABLE 3A Materials Added Magnesium Methyl Distilled aluminum Gellancellulose Water Example silicate (%) gum (%) (%) (%) 11 0.22 0 0 Q.S. 120 0.06 0 Q.S. 13 0 0 2.36 Q.S. 14 0.22 0.06 0 Q.S. 15 0.22 0 2.35 Q.S.16 0 0.05 2.36 Q.S. 17 0.22 0.05 2.35 Q.S.

TABLE 3B Suspension System of Finished Product Magnesium Methyl aluminumGellan cellulose 25° C. Initial Viscosity (cps) Example silicate (%) gum(%) (%) 0.1 s⁻¹ 1 s⁻¹ 10 s⁻¹ 20 s⁻¹ 100 s⁻¹ 11 0.1 0 0 7 1 1 1 1 12 00.25 0 268 125 47 33 14 13 0 0 1.086 3712 2774 1591 1286 734 14 0.1 0.250 667 173 49 34 14 15 0.1 0 1.086 5185 3780 2041 1619 887 16 0 0.251.086 18780 7446 2901 2165 1052 17 0.1 0.25 1.086 33110 11980 4147 29841405

Surprisingly, the suspension system in Example 17, which is equivalentto a finished product containing 0.1% magnesium aluminum silicate,0.025% gellan gum, 1.086% methyl cellulose, had the highest initialviscosity at 0.1 s⁻¹. This value was significantly higher than any othersuspension system tested, which indicates that there may be asynergistic effect when these three components are used in a suspensionsystem.

Furthermore, Example 13, where the suspension system only containsmethyl cellulose, is significantly higher than Examples 11 and 12, wherethe suspension system only contains magnesium aluminum silicate andgellan gum, respectively. However, when methyl cellulose is combinedwith a small amount of magnesium aluminum silicate, as in Example 15, orgellan gum, as in Example 16, the initial viscosity at 0.1 s⁻¹ shearrate is significantly higher than methyl cellulose alone.

It is also surprising that gellan gum had only a slight effect on theformulation's initial viscosity in the mid to high shear range (greaterthan or equal to 10 s⁻¹ shear rate) but had a large effect on theinitial low shear (0 s⁻¹ shear rate to 1 s⁻¹ shear rate).

In one example, the initial viscosity at 0.1 s⁻¹ shear rate is greaterthan about 1000 cps, in another example greater than about 2000 cps, inanother example greater than about 3000 cps, in another example greaterthan about 3500 cps, in another example greater than about 4000 cps, inanother example greater than about 4500 cps, in another example greaterthan about 5000 cps, in another example greater than about 10,000 cps,in another example greater than about 15,000 cps, in another examplegreater than about 18,500 cps, in another example greater than about19,000 cps, in another example greater than about 21,000 cps, in anotherexample greater than about 25,000 cps, in another example greater thanabout 28,000 cps, in another example greater than 30,000 cps, and inanother example greater than about 32,000 cps. In another example, theinitial viscosity at 0.1 s⁻¹ shear rate is from about 5000 cps to about40,000 cps, in another example from about 8,000 cps to about 37,000 cps,in another example from about 10,000 cps to about 35,000 cps, and inanother example from about 18,000 cps to about 33,500 cps. In anotherexample, the initial viscosity at 0.1 s⁻¹ shear rate is from about 1000cps to about 26,000 cps, in another example from about 2,000 cps toabout 15,000 cps, in another example from about 4,000 cps to about10,000 cps, and in another example from about 5,000 cps to about 6,000cps. The initial viscosity can be determined by the Rheology TestMethod, described hereafter.

In another example, the viscosity throughout the shelf life of thecomposition at 0.1 s⁻¹ shear rate is greater than about 100 cps, inanother example greater than 250 cps, in another example greater thanabout 500 cps, in another example greater than about 750 cps, in anotherexample greater than about 1000 cps, in another example greater thanabout 2000 cps, in another example greater than about 4000 cps, inanother example greater than about 5000 cps, in another example greaterthan about 7000 cps, and in another example greater than about 10,000cps. In another example, the viscosity at the end of the shelf life at0.1 s⁻¹ shear rate can be from about 500 cps to about 15,000 cps, inanother example from about 1000 cps to about 13,000 cps, in anotherexample from about 3000 cps to about 9,000 cps, and in another examplefrom about 4000 cps to about 7000 cps. The initial viscosity can bedetermined by the Rheology Test Method, described hereafter.

Table 4A, below, shows the sedimentation after 30 days at 40° C. offormulations with varying suspension systems. Table 4B, below, shows thecomposition of Examples A-Q.

TABLE 4A Suspension System Magnesium Description of aluminumSedimentation silicate Gellan Methyl after 30 days Example (%) gum (%)cellulose (%) at 40° C. A 0.1 0.025 1.086 Slight sediment B 0.1 0.0251.3 Slight sediment C 0.1 0.03 1.193 Slight sediment D 0.1 0.035 1.3 Nosediment E 0.1 0.035 1.086 Slight sediment F 0.125 0.025 1.193 Veryslight sediment G 0.125 0.03 1.086 No sediment H 0.125 0.03 1.193 Nosediment I 0.125 0.03 1.3 No sediment J 0.125 0.03 1.193 Slight sedimentK 0.125 0.035 1.193 No sediment L 0.15 0.025 1.086 No sediment M 0.150.025 1.3 No sediment N 0.15 0.025 1.086 No sediment O 0.15 0.03 1.193No sediment P 0.15 0.035 1.3 No sediment Q 0.15 0.035 1.086 Slightsediment

TABLE 4B Examples A-Q BSS 1.7305% Suspension System See Table 4A BenzoicAcid  0.025% Salicylic Acid 0.0749% Sodium Salicylate 0.0559% Sweetener0.0612% Color 0.0124% Flavor  0.088% Distilled Water Q.S.

Table 4A shows that even though methyl cellulose had the largest effecton the formulation's initial viscosity, it may not provide physicalstability with respect to the suspension. However, if the formulationincludes a low level of magnesium aluminum silicate, the formulation canhave better suspension stability. This is especially surprising becausemagnesium aluminum silicate had very little effect on the formulation'sinitial viscosity. Table 4 shows that most of the formulations that hadmagnesium aluminum silicate at or above 0.15%, had no sediment. Whilenot wishing to be bound by theory, it is believed that magnesiumaluminum silicate, is playing an important role in particle to particleinteractions that is keeping the bismuth, as well as other components,suspended and/or enabling easier resuspension upon mixing/shaking.

The sedimentation can be determined by a visual observation method thatcan be performed as follows. The liquid pharmaceutical formulation isstored in a full PET bottle that can hold 8 fluid ounces (240 mL) for 30days at 40° C. The bottles are stored closed in a room and not exposedto sunlight. The bottles are not shaken or moved during this period.After 30 days, the bottle is slowly inverted and a person looks throughthe bottle to see if any sedimentation is visually perceptible. As usedherein, “visually perceptible” means that a human viewer can visuallydiscern the sedimentation with the unaided eye (excepting standardcorrective lenses adapted to compensate for near-sightedness,farsightedness, or stigmatism, or other corrected vision) in lighting atleast equal to the illumination of a standard 100 watt incandescentwhite light bulb at a distance of 6 inches (15.24 cm).

In one example, the liquid formulation has no more than slightsedimentation that is visually perceptible. In another example, theliquid formulation has no sedimentation that is visually perceptible.

Table 5 shows the pH change at 0, 30, 60, 90, and 180 days when theliquid pharmaceutical product is stored at 40° C., 75% relative humidity(RH) for 180 days. Table 5B shows the composition of Examples 18 and 19.

TABLE 5A pH after being stored at 40° C./75% RH Example SuspensionSystem 0 days 30 days 60 days 90 days 180 days 18 0.1% magnesiumaluminum 3.5 3.8 3.9 3.9 4.0 silicate, 1.086% methyl cellulose, 0.025%gellan gum 19 1.086% methyl cellulose, 3.2 3.3 3.3 3.3 3.2 0.0375%gellan gum

TABLE 5B Examples 18-19 BSS 1.7305% Suspension System See Table 5ABenzoic Acid  0.025% Salicylic Acid 0.0749% Sodium Salicylate 0.0559%Sweetener 0.0612% Color 0.0124% Flavor  0.088% Distilled Water Q.S.

The examples in Table 5A shows that Example 18, which was formulatedwithout magnesium aluminum silicate, essentially eliminated the pH driftover a 180 day period when stored at 40° C. and 75% RH. Thus, in somecircumstances it may be beneficial to formulate without magnesiumaluminum silicate and use a suspension system that includes gellan gumand/or methyl cellulose. The pH drift in Example 19 can also lead to animproved shelf life over current formulations.

The pH can be calculated using the pH Test Method as described below.The solution is stored upright in closed PET bottles and are not exposedto sunlight.

Examples 20-25, as shown in table 6 below, were made as follows. First,three premixes or slurries were made. The dye premix was made by addingcolor to water and heating and stirring until dissolved.

Separately, a minors premix was made by adding the flavor, salicylicacid, sodium salicylate, sweeteners, benzoic acid, and sorbic acid towater and heating and stirring until the solution became clear.

Separately, a BSS slurry was made by adding BSS powder to water underhigh shear.

To make the examples, the first step was to add the minors premix towater. Then, the suspension system components were added to water underhigh shear mixing: gellan gum, magnesium aluminum silicate, and finallymethyl cellulose. Then, under low shear mixing the dye premix and thenthe BSS slurry were added. Then Q.S. of water was added to form thefinal bismuth-containing pharmaceutical formulation.

TABLE 6 Ex. 20 Ex. 21 Ex. 22 Ex. 23 Ex. 24 Ex. 25 BSS  1.716%  1.716% 1.716%  1.716%  1.716%  1.716% Methyl cellulose   1.3%   1.3%   1.3%  1.3%   1.3%   1.0% Magnesium  0.11%  0.11%  0.11%  0.22%  0.11%  0.22%aluminum silicate Gellan gum  0.035%  0.035%  0.07%  0.07%   0.1%   0.1%Benzoic Acid 0.0746% 0.0746% 0.0746% 0.0746% 0.0746% 0.0746% Sorbic Acid0.0373% 0.0373% 0.0373% 0.0373% 0.0373% 0.0373% Salicylic acid  0.050% 0.050%  0.050%  0.050%  0.050%  0.050% Sodium 0.0847% 0.0847% 0.0847%0.0847% 0.0847% 0.0847% Salicylate Sweetener 0.0612% 0.0612% 0.0612%0.0612% 0.0612% 0.0612% Color 0.0062% 0.0062% 0.0062% 0.0062% 0.0062%0.0062% Flavor 0.0888% 0.0888% 0.0888% 0.0888% 0.0888% 0.0888% DistilledWater Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

pH Test Method

First, calibrate the Thermo Scientific™ Orion™ 710A pH meter using themanufacturer's instructions for autocalibration. Select two buffersolutions for calibration whose difference in pH does not exceed 4 pHunits (i.e. 1.68 and 4; 4 and 7). If it is necessary to measure sampleswhose pH encompass multiple ranges (i.e. 3.5 and 4.5) a three-pointcalibration curve is necessary.

Place a suitable quantity of a neat sample to be tested in a beaker atambient temperature. Enough solution should be used to cover electrodetips and liquid junction completely. Lower the electrodes into positionand stir with a magnetic stirbar while measuring the pH. Agitationshould be vigorous enough to mix the solution thoroughly withoutwhipping air into it.

After each usage the electrode should be washed free from the samplesolution with deionized water. Blot the pH electrode with an absorbenttissue—do not rub. When not in use, store the electrode in storagesolution recommended in the instruction manual or in buffer with a pH ofless than 7 buffer and keep the internal solution filling port capped toreduce evaporation.

Rheology Test Method

TA Instrument AR 200 Rheometer (available from TA Instruments, NewCastle, Del.) with a couette setup (cup and bob), Stainless SteelStandard DIN or concentric cylinder. The inner radius is 15.18 mm, therotor outer radius is 14.01 mm, the cylinder immersed height is 42.02mm, and the gap is 5920 μm.

The test is run at 25° C. with a 23 mL sample. The procedure is run witha stepped flow from 0.0100 s⁻¹ shear rate to 100.0 s⁻¹ shear rate at 10points/decade.

Values disclosed herein as ends of ranges are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each numerical range is intended to meanboth the recited values and any integers within the range. For example arange disclosed as “1 to 10” is intended to mean “1, 2, 3, 4, 5, 6, 7,8, 9, 10.”

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm.”

All percentages and ratios used herein are by weight unless otherwisespecified, and all measurements are made at 25° C. unless otherwisespecified.

Every document cited herein, including any cross referenced or relatedpatent or application and any patent application or patent to which thisapplication claims priority or benefit thereof, is hereby incorporatedherein by reference in its entirety unless expressly excluded orotherwise limited. The citation of any document is not an admission thatit is prior art with respect to any invention disclosed or claimedherein or that it alone, or in any combination with any other referenceor references, teaches, suggests or discloses any such invention.Further, to the extent that any meaning or definition of a term in thisdocument conflicts with any meaning or definition of the same term in adocument incorporated by reference, the meaning or definition assignedto that term in this document shall govern.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

What is claimed is:
 1. A liquid pharmaceutical suspension for oraladministration comprising: a. a bismuth-containing pharmaceutical agent;b. a suspension system comprising from about 0.005% to about 1% gellangum; and c. water.
 2. The liquid pharmaceutical suspension of claim 1wherein the gellan gum comprises high acyl gellan gum.
 3. The liquidpharmaceutical suspension of claim 1 wherein the suspension systemfurther comprises from about 0.1% to about 5% methyl cellulose.
 4. Theliquid pharmaceutical suspension of claim 1 wherein the suspensionsystem comprises from about 0.01% to about 1% magnesium aluminumsilicate.
 5. The liquid pharmaceutical suspension of claim 1 wherein thesuspension system comprises from about 0.01% to about 0.75% gellan gum.6. The liquid pharmaceutical suspension of claim 5 wherein the gellangum comprises high acyl gellan gum.
 7. The liquid pharmaceuticalsuspension of claim 6 comprising from about 0.2% to about 8%bismuth-containing pharmaceutical agent.
 8. The liquid pharmaceuticalsuspension of claim 7 wherein the suspension system comprises from about0.01% to about 0.6% magnesium aluminum silicate.
 9. The liquidpharmaceutical suspension of claim 8 wherein the suspension systemfurther comprises from about 0.1% to about 5% methyl cellulose.
 10. Theliquid pharmaceutical suspension of claim 5 wherein the suspensionsystem comprises from about 0.01% to about 0.5% gellan gum.
 11. Theliquid pharmaceutical suspension of claim 9 wherein the suspensionsystem comprises from about 0.015% to about 0.15% gellan gum.
 12. Theliquid pharmaceutical suspension of claim 11 wherein the suspensionsystem comprises from about 0.02% to about 0.05% gellan gum.
 13. Theliquid pharmaceutical suspension of claim 1 further comprising apreservative comprising benzoic acid.
 14. A liquid pharmaceuticalsuspension for oral administration comprising: a. a bismuth-containingpharmaceutical agent; b. a suspension system comprising gellan gum andmethyl cellulose; and c. water.
 15. The liquid pharmaceutical suspensionof claim 14 wherein the suspension system comprises about 0.1% to about5% methyl cellulose.
 16. The liquid pharmaceutical suspension of claim14 wherein the suspension system further comprises about 0.01% to about0.6% magnesium aluminum silicate.
 17. The liquid pharmaceuticalsuspension of claim 14 wherein the suspension system comprises fromabout 0.01% to about 0.15% gellan gum.
 18. The liquid pharmaceuticalsuspension of claim 17 wherein the gellan gum comprises high acyl gellangum.
 19. The liquid pharmaceutical suspension of claim 14 wherein thesuspension system comprises from about 0.01% to about 1% gellan gum. 20.The liquid pharmaceutical suspension of claim 19 wherein the suspensionsystem comprises about 0.05% to about 0.6% magnesium aluminum silicate.